Background: C. difficile infection (CDI) is increasing in incidence and severity; CDI affects 500,000 Americans each year, causes 20,000 deaths annually, and imposes a significant financial burden on healthcare institutions. Preventing CDI is essential, and the VA Multidrug Resistant Organism (MDRO) Program Office recently mandated a bundle for prevention of CDI in VA facilities. The bundle includes appropriate diagnostic testing, optimization of hand hygiene compliance, contact isolation for CDI, and environmental cleaning of rooms of patients with CDI. However, it does not address optimum implementation strategies to ensure successful application of these interventions, nor does it prescribe how these measures may be undertaken. Implementing and adhering to these recommended measures varies considerably across institutions. Specific Aims: The central hypothesis of this project is that variation in practices and approaches related to environmental cleaning?particularly daily cleaning?will emerge as major contributors to variable implementation of the CDI bundle and CDI rates. The rationale stems from the literature identifying frequent environmental contamination with C. difficile and the findings of our pilot work. Our objective is to assess work system barriers and facilitators to bundle implementation using a mixed-methods approach. The specific aims for this project are: 1. To evaluate the association between existing CDI bundle implementation and CDI rates at 10 VA sites. 2. To identify practices that facilitate or impede CDI bundle implementation at 10 VA sites. 3. Pilot and finalize tools to improve environmental cleaning at one VA site using the rapid plan-do-study- act cycle methodology of quality improvement. Methods: We will use the innovative Systems Engineering Initiative for Patient Safety (SEIPS) 2.0 model of work system and patient safety as the study framework integrated with the iPARiHS framework. This model, as well as general literature on guideline implementation, will guide interview questions. Participants will include nurses, physicians, patients, environmental services and hospital leadership. We will conduct direct observations of healthcare workers based on the SEIPS 2.0 model. We will observe patient rooms, individuals, tasks, and organization to better understand the overall work system that surrounds the process of care for CDI patients. Impact: Prevention of Clostridium difficile is a priority of the VA, and implementation of a C. difficile prevention bundle, akin to an already established methicillin-resistant Staphylococcus aureus (MRSA) bundle, has recently been rolled out nationally. However, our ability to devise and implement strategies for containment of C. difficile is hampered by a limited understanding of factors influencing acquisition, spread, and prevention of C. difficile in VA facilities. Immediate benefits of achieving the objectives of this proposal will be generation of important data regarding barriers and facilitators of implementation using a systems engineering approach. Our study will produce data, methods, and tools that have widespread relevance and portability, with the potential to reduce healthcare-associated infections (HAIs) including but not limited to C. difficile infection. This is the first research study to systematically examine barriers and facilitators of implementation of a prevention bundle for CDI. Our project is innovative in that it will employ the SEIPS 2.0 framework to undertake a complete work systems analysis for CDI prevention; use a number of complementary approaches to data collection; and consider not just healthcare workers involved in direct patient care, but also ancillary staff who are critical to successful CDI prevention. Our study methods and approach may be widely used not just for CDI but also other HAIs, and will add to the fields of patient safety and infection control.